Tuberculosis (TB) chemotherapy often fails to sterilize Mycobacterium tuberculosis (Mtb) resulting in individuals at risk of relapse TB. The mechanisms that allow Mtb to survive during paucibacillary persistent TB infections are for the most part unknown. Drug treatment and silencing of in vivo essential genes can cure acute and chronic Mtb infections in mice to the extent that CFU can no longer be detected on agar plates. However, as in humans, Mtb in these mice is often not sterilized and paucibacillary persistence eventually results in relapse of TB. We propose to develop a new animal model of paucibacillary persistence and use this model to identify the processes that Mtb requires to persist following apparent eradication. The proposed experiments will increase understanding of the mechanisms leading to paucibacillary persistence and will establish a model for studying paucibacillary disease and relapse in mice.